Stories about: optic nerve damage

Optic nerve regeneration: One approach doesn’t fit all

alpha retinal ganglion cells optic nerve regeneration
Alpha-type retinal ganglion cells (RGCs) in part of an intact mouse retina. The cell axons lead to the optic nerve head (top right) and then exit into the optic nerve. The alpha RGCs are killed by the transcription factor SOX11 despite its pro-regenerative effect on other types of RGCs. (Fengfeng Bei)

Getting a damaged optic nerve to regenerate is vital to restoring vision in people blinded through nerve trauma or disease. A variety of growth-promoting factors have been shown to help the optic nerve’s retinal ganglion cells regenerate their axons, but we are still far from restoring vision. A new study published yesterday in Neuron underscores the complexity of the problem.

A research team led by Fengfeng Bei, PhD, of Brigham and Women’s Hospital, Zhigang He, PhD, and Michael Norsworthy, PhD, of Boston Children’s Hospital, and Giovanni Coppola, MD, of UCLA conducted a screen for transcription factors that regulate the early differentiation of RGCs, when axon growth is initiated. While one factor, SOX11, appeared to be critical in helping certain kinds of RGCs regenerate their axons, it simultaneously killed another type — alpha-RGCS (above)— when tested in a mouse model.

At least 30 types of retinal ganglion cell message the brain via the optic nerve. “The goal will be to regenerate as many subtypes of neurons as possible,” says Bei. “Our results here suggest that different subtypes of neurons may respond differently to the same factors.”

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Zinc chelation: A better way to regenerate the optic nerve?

optic nerve zinc chelation

For more than two decades, researchers have tried to regenerate the injured optic nerve using different growth factors and/or agents that overcome natural growth inhibition. They’ve had partial success, sometimes even restoring rudimentary elements of vision in mouse models.

But at best, these methods get only about 1 percent of the injured nerve fibers to regenerate and reconnect the retina to the brain. That’s because most of the damaged cells, known as retinal ganglion cells (RGCs), eventually die, says Larry Benowitz, PhD, of the F.M. Kirby Neurobiology Center at Boston Children’s Hospital.

Benowitz and colleagues now show a surprising new approach that gets RGCs to live longer and regenerate robustly: using chelating agents to bind up zinc that’s released as a result of the injury.

These studies, too, were done in mice. If the findings hold up in human studies, they could spell hope for people with optic nerve injury due to trauma, glaucoma or other causes, and possibly even spinal cord injury.

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Drug ‘cocktail’ could restore vision in optic nerve injury

regenerating optic nerves cropped
Gene therapy achieved extensive optic nerve regeneration, as shown in white, but adding a potassium channel blocking drug was the step needed to restore visual function. In the future, it might be possible to skip gene therapy and inject growth factors directly. (Fengfeng Bei, PhD, Boston Children’s Hospital)

When Zhigang He, PhD, started a lab at Boston Children’s Hospital 15 years ago, he hoped to find a way to regenerate nerve fibers in people with spinal cord injury. As a proxy, he studied optic nerve injury, which causes blindness in glaucoma — a condition affecting more than four million Americans — and sometimes in head trauma.

By experimenting with different growth-promoting genes and blocking natural growth inhibitors, he was able to get optic nerve fibers, or axons, to grow to greater and greater lengths in mice. But what about vision? Could the animals see?

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Fast-regenerating mice offer clues for stroke, spinal cord and optic nerve injury

axon regeneration CNS
The CAST mouse from Thailand–genetically distinct from most lab mice–may have the right ingredients for nerve regeneration. (Courtesy Jackson Laboratory)

Second in a two-part series on nerve regeneration. Read part 1.

The search for therapies to spur regeneration after spinal cord injury, stroke and other central nervous system injuries hasn’t been all that successful to date. Getting nerve fibers (axons) to regenerate in mammals, typically lab mice, has often involved manipulating oncogenes or tumor suppressor genes to encourage growth, a move that could greatly increase a person’s risk of cancer.

A study published online last week by Neuron, led by the F.M. Kirby Neurobiology Center at Boston Children’s Hospital, took a completely different tactic.

Seeing little success at first, the researchers wondered whether they were working with the wrong mice.

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Proteomics provides new leads into nerve regeneration

Nerve regeneration. From Santiago Ramón y Cajal’s “Estudios sobre la degeneración y regeneración del sistema nervioso” (1913-14). Via Scholarpedia.

nerve regeneration proteomicsFirst in a two-part series on nerve regeneration. Read part 2

Researchers have tried for a century to get injured nerves in the brain and spinal cord to regenerate. Various combinations of growth-promoting and growth-inhibiting molecules have been found helpful, but results have often been hard to replicate. There have been some notable glimmers of hope in recent years, but the goal of regenerating a nerve fiber enough to wire up properly in the brain and actually function again has been largely elusive.

“The majority of axons still cannot regenerate,” says Zhigang He, PhD, a member of the F.M. Kirby Neurobiology Center at Boston Children’s Hospital. “This suggests we need to find additional molecules, additional mechanisms.”

Microarray analyses—which show what genes are transcribed (turned on) in injured nerves—have helped to some extent, but the plentiful leads they turn up are hard to analyze and often don’t pan out. The problem, says Judith Steen, PhD, who runs a proteomics lab at the Kirby Center, is that even when the genes are transcribed, the cell may not actually build the proteins they encode.

That’s where proteomics comes in. “By measuring proteins, you get a more direct, downstream readout of the system,” Steen says.

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First light: Vision restored in blind mice

Regenerating nerve fibers from the retina (shown in red) are seen coming into the dorsal lateral geniculate nucleus, a principal visual relay area of the brain.

Some kinds of vision loss are reversible: Lucentis and Avastin can restore some visual acuity in macular degeneration, and gene therapy in the eye has had success in genetic forms of blindness like Leber’s hereditary neuropathy, affecting light receptors in the retina. But when the optic nerve is damaged – from a traumatic injury or from glaucoma — all bets are off. The eyes may take in visual information, but it can’t get to the brain. It’s the end of the road.

Larry Benowitz, PhD, and other neurobiologists at Boston Children’s Hospital and elsewhere have tried for years to rebuild that road. Regeneration of the optic nerve, and in the central nervous system in general, was once thought impossible. But through patient tinkering to coax natural growth signals and silence growth-inhibiting signals, neurons in the retina – known as retinal ganglion cells — began to grow a bit into the optic nerve. Then a bit more.

In a 2010 paper, Benowitz’s team combined their top three interventions, and showed a synergistic effect – the greatest growth of optic nerve fibers (axons) to date. But no one had been able to demonstrate recovery of vision after severe optic nerve damage – until now.

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